Sex and genetics affect fatty-liver development

Published February 01 2017

By Alexandra Nail

The obesity epidemic has accelerated the prevalence of liver disease in the Western world. Nonalcoholic fatty liver disease is caused by fat accumulation, also known as steatosis, in hepatocytes, the primary cell type in the liver. If left untreated, NAFLD can lead to end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma.

Males and females develop NAFLD differently, and the molecular mechanisms by which genetic factors influence NAFLD development in both sexes are not fully understood. In a Journal of Lipid Research, Jake Lusis and colleagues at the University of California, Los Angeles, and at the University of Wisconsin–Madison used genetically identical strains of mice to determine how sex differences at the genetic level contribute to the development of hepatic steatosis.

In a previous study published in 2015, Lusis and colleagues analyzed 113 mouse strains to identify molecular pathways upregulated in males more susceptible to NAFLD. In the JLR study, the investigators evaluated 100 strains of female mice for NAFLD susceptibility. “In the past, studies focused on males and were often applied to women without any reflection on gender-specific differences,” says Lusis. “We hope this study will prompt other researchers to include both genders in their work.”

To identify factors contributing to hepatic steatosis in females, Lusis and colleagues measured lipid accumulation in the liver and other tissues after mice were fed a diet high in fat and sucrose. This type of diet mimics a typical Western diet. Triglycerides, which make up the main component of fat, were lower in female livers compared with male livers. In addition, the locations where the mice stored fat and the differences in plasma lipids with respect to hepatic triglycerides correlated differently between the sexes. These data suggest that gender-based lipid metabolism influenced fatty-liver development.

The investigators next did microarray analyses to identify gene expression profiles that correlated with hepatic triglyceride content. This technology relies on hybridization of gene-specific probes to quantify expression of numerous genes in multiple samples. Roughly two-thirds of the genes that correlated to hepatic triglyceride content were shared between sexes. A significant portion of these genes were associated with mitochondria, highlighting the importance of mitochondrial function in lipid metabolism for both sexes.

To determine how genetic variation might affect differences between the sexes in hepatic triglyceride accumulation, Lusis and colleagues carried out a genomewide association study. The study analyzed single nucleotide polymorphisms to identify genetic loci that associate with differences in hepatic triglyceride content and, consequently, NAFLD development. The investigators found a high correlation between S-phase kinase protein 1a expression and hepatic triglyceride levels in females. Previous work by Lusis and colleagues showed that glycerophosphodiester phosphodiesterase 1 is important for NAFLD development in males. Lusis notes, “Different genes might be more important for development of fatty liver in one sex than in the other.”

To test whether sex hormones are responsible for sex-biased differences in hepatic triglyceride accumulation, the investigators removed the reproductive organs responsible for sex-hormone production from the mice. When normalized to body fat content, gonadectomized males on a high-fat, high-sucrose diet exhibited increased hepatic triglyceride content, whereas their female counterparts showed no differences. Previous studies had identified that ovariectomy increased insulin resistance in both normal and high-fat-fed females. Taken together, these data suggest that estrogen is protective against insulin resistance in females and that testosterone is protective against hepatic triglyceride accumulation in males.

Current strategies to control NAFLD include weight reduction, lifestyle changes, and pharmacological agents to increase insulin sensitivity or decrease cholesterol levels. So what’s in store for the future for NAFLD research and treatment? “We hope that more detailed follow-up studies of the genes identified in our work will result in a better understanding of the disease process and will lead to the development of medications against NAFLD,” says Lusis.